The liver is an essential organ for life with multiple important functions. Upon receiving various types of injury, hepatocytes, the parenchymal epithelial cells in the organ, show prompt regenerative response by undergoing proliferation and hypertrophy, thereby recovering the lost tissue structure and function. However, no one has ever observed such dynamic behavior of hepatocytes in real-time in living animals.

The bile produced in hepatocytes is collected in bile canaliculi, which connect to epithelial tubular structures called the bile duct, consisting of biliary epithelial cells (BECs). Bile ducts in the liver form tree-like structures with many small branches, and serve primarily as the conduit for biliary excretion. At the same time, the biliary system can also be recognized as the pool and/or niche for the liver stem/progenitor cells (LPCs) that can contribute to regeneration of the damaged liver parenchyma by differentiating to hepatocytes under certain conditions. We recently developed a novel technique that can visualize the 3D structure of the whole biliary tree within mouse liver samples. Using this original method, we have revealed that the biliary system possesses a unique and unprecedented structural flexibility whose dynamic and adaptive remodeling constitutes the basis for robust liver regeneration.

Here, we extend this 3D structural analysis to even higher dimensional imaging studies and try to elucidate the liver epithelial tissue dynamics in regeneration and homeostasis.

In this research project, we try to understand how the structure and functions of the liver epithelial cells (i.e., hepatocytes and BECs/LPCs) change according to various types of liver stress and damage conditions. Using multiphoton laser scanning microscopy in combination with different types of fluorescent probes for monitoring various cellular functions, we perform intravital multidimensional (i.e., 3D + time + cellular function) analyses of these cell types in the mouse liver. We'll also try to unveil the underlying cellular and molecular mechanisms regulating their dynamic behavior.

Our current project based on the cutting-edge technology for imaging of cellular dynamics in living animals is expected to lead to construction and establishment of a whole new picture of the liver epithelial tissues and the precise understanding of their regulatory mechanisms. This will not only lead to significant progress in the field of liver biology, but also serve as a paradigm for future studies in the field of developmental and regenerative biology as well as of "Tubulology" in general. Our study will also contribute to better understanding of the mechanisms of liver and biliary diseases and development of therapies to conquer them.